HTLV-1による細胞がん化の分子機構

• 研究課題/領域番号: 06280103
• 研究種目: 重点領域研究
• 配分区分: 補助金
• 研究機関: 東北大学
• 研究代表者: 菅村 和夫 東北大学, 医学部, 教授 (20117360)
• 研究分担者: 渡邊 俊樹 東京大学, 医科学研究所, 助教授 (30182934) ; 内山 卓 京都大学, ウイルス研究所, 教授 (80151900) ; 藤澤 順一 (藤沢 順一) 関西医科大学, 医学部, 教授 (40181341) ; 赤城 剛 国立がんセンター研究所, ウイルス部, 研究員 (90184077) ; 藤井 雅寛 東京医科歯科大学, 医学部, 助教授 (30183099) ; 吉木 敬 北海道大学, 医学部, 教授 (60220612)
• 研究期間 (年度): 1994 – 1996
• 研究課題ステータス: 完了 (1996年度)
• 配分額: 108,000千円 (直接経費: 108,000千円); 1996年度: 36,000千円 (直接経費: 36,000千円); 1995年度: 35,000千円 (直接経費: 35,000千円); 1994年度: 37,000千円 (直接経費: 37,000千円)
• キーワード: 成人T細胞白血病 / HTLV-1 / 転写活性化 / HTLV-I / HAM / 転写活性化因子 / トランスフォーメイション / ATL / Tax / トランスジェニックラット / SCIDマウス

研究概要

細胞の不死化およびがん化におけるHTLV-1の役割について、特にその転写活性化因子であるTaxの機能を中心に解析し、以下の研究成果が得られた。
1。Taxの新たな標的遺伝子としてSLP76を同定した。SLP76はT細胞抗原受容体を介するNFAT活性化ひいてはIL-2発現誘導に関わっている可能性が示唆された。
2。HTLV-1感染T細胞がFas誘導アポトーシスに対して抵抗性を示すことを明らかにした。この抵抗性にはTax発現とFas-associated phosphatase(FAP-1)が関わっていることが示唆された。
3。Tax変異体を用いた解析から、TaxによるT細胞増殖亢進がTaxによるNFkB活性化を介したIL-2Rα鎖の発現誘導と相関することを明らかにした。
4。TaxによるRat-1細胞トランスフォーメーションと相関して発現増強する遺伝子として、cyclophilin C-associated protein(CyCAP)を同定した。
5。HTLV-1プロウイルスTaxの一次構造多様性と転写活性化能とを調べ、40-70%のクロンにアミノ酸置換を含む塩基置換が証明された。
6。HTLV-I感染細胞と血管内皮細胞の接着分子としてOX40を同定した。ATL白血病細胞、さらにそれらの皮膚浸潤細胞にもOX40が発現することを証明した。
7。HTLV-I感染細胞に発現がみられるCD30の細胞内領域にTRAF2、TRAF5が会合し、NFkB活性化に関与していることを証明した。
HAMラットの脊髄の病理組織学的解析から、欠突起細胞のアポトーシス、TaxやTNFαの発現ならびにbcl-2の発現抑制が観察された。

研究成果

• [文献書誌] 竹下 敏一: "A new type of signal transducing adaptor molecule, STAM : Association with Janus kinases and involvement in cell growth and c-myc induction mediated by cytokines." Immunity. (印刷中).
• [文献書誌] 竹下 敏一: "Cloning of a novel signal transducing adaptor molecule, STAM : containing an SH3 and ITAM." Bioch. Biophys. Res. Comm.225. 1035-1039 (1996)
• [文献書誌] 菅村 和夫: "The interleukin 2 receptor γ chain : its role in the multiple cytokinereceptor complexes and T cell development in XSCID." Annu. Rev. Immunol.14. 179-205 (1996)
• [文献書誌] 東村 紀一: "Induction of OX40, a receptor of gp34, on T cells by trans-acting transcriptional activation, Tax, of human T-cell leukemia virus type I." Jpn. J. Caner Res.87. 227-231 (1996)
• [文献書誌] 藤井 雅寛: "Selective activation of the proto-oncogane c-jun promoter by the transforming protein of v-Rel." Oncogene. 12. 2193-2202 (1996)
• [文献書誌] 赤城 剛: "Expression of cell-cycle regulatory genes in HTLV-1 infected T-cells : Possible involvement of Taxl in the altered expression of cyclin D2, pI8lnk4, and p21Wafl/Cipl/SdiI." Oncogene. 12. 1645-1652 (1996)
• [文献書誌] Ohbo,K: "Functional analysis of the human interleukin 2 receptor γ chain gene promoter." J.Biol.Chem. 13. 7479-7486 (1995)
• [文献書誌] Ohbo,K: "Modulation of hematopoiesis in mouse with a truncated mutant of the interleukin-2 receptor γ chain." Blood. (in press).
• [文献書誌] Higashimura,N.: "Indution of OX40,a receptor of gp34,on T cells by Trans-acting transcriptional activator,Tax,of human T-cell leukemia virus type I." Jpn.J.Caner Res.(in press).
• [文献書誌] Fujii,M: "c-Jun,c-Fos and their family members activate the transcription mediated by three 21bp repetitive sequences in the HTLV-I long terminal repeat." Intervirol.(in press).
• [文献書誌] Fujii,M: "Identification of the Tax interactuion region of serum response factor that mediates the abberant induction of imediate early genes through CArG boxes by HTLV-I Tax." Oncogene. 11. 7-14 (1995)
• [文献書誌] Matsuzaki,Y.: "Identification of transcriptional activation domain of TREB3,a CREB/ATF family protein that binds to HTLV-I enhancer." J.Biochem.117. 303-308 (1995)
• [文献書誌] Murakami,T.: "HTLV-I tax enhancer NF-Kapper-B2 expression and binds to the products p52 and p100,but does not suppress the inhibitory function of p100." Virology. 206. 1066-1074 (1995)
• [文献書誌] Yamaoka,S.: "Constitutive activation of NF-kB is essential for transformation of rat fibroblasts by the human T-cell leukemia virus tyoe I Tax protein." EMBOJ.(in press).
• [文献書誌] Akagi,T.: "Characterization of T-cells immortalized by Tax of human T-cell leukemia virus type 1." Blood. 87(in press).
• [文献書誌] Akagi,T,: "Increased Protein tyrosine-Phosphorylation in primary T-cells transformed with Tax1 of human T-cell leukemia virus Type I." FEBS Lett.358. 34-38 (1995)
• [文献書誌] Imada,K.: "Tumorigenicity of human T-cell leukemia virus type I-infected cell lines in severe combined immunodeficient mice and characterization of the cells proliferating in vivo." Blood. 86. 2350-2357 (1995)
• [文献書誌] Uchiyama,T.: "Adhesion properties of adult T cell leukemia cells." Leukemia and Lymphoma. 16. 407-412 (1995)
• [文献書誌] Takaori-Kondo.A.: "Detection of homing,proliferation,and infiltration sites of adult T cell leukemia cells in severe combined immunodeficiency mice using radiometric techniques." Jpn.J.Cancer Res.86. 322-328 (1995)
• [文献書誌] Hosono,M.: "Radioimmunodetection of human leukemia with anti-interleukin-2 receptor antibody in severe combined immunodeficiency mice." Nuclear medicine and Biology. 22. 869-874 (1995)
• [文献書誌] Seto,K.: "A ral model of HTLV-I intection.Development of chronic progressive myelopathy in seropositive WKAH rats and related apotosis." Acta Neuropathl.89. 483-490 (1995)
• [文献書誌] Yamada,S.: "Cytokine-producing mammary carcinomas in transgenic rats carrying the pX gene of human T-lymphotropic virus type I." Cancer Res.55. 2524-2527 (1995)
• [文献書誌] Takeuchi,K.: "Expression of endogenous retroviruses,ERV3 and λ4-1,in synovial tissues from patients with rheumatoid arthritis." Clin.Exp.Immunol.99. 338-344 (1995)
• [文献書誌] Kondo,M.: "Functional participation of the IL-2 receptor γ chain in IL-7 receptor complexes." Science. 263. 1453-1454 (1994)
• [文献書誌] Ishii,N.: "Impairment of ligand binding and growth signaling of mutant IL-2 receptor γ chains in patients with X-linked severe combined immunodeficiency." J.Immunol.153. 1310-1317 (1994)
• [文献書誌] Tanaka,N.: "Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor β and γ chains." Proc.Natl.Acad.Sci.USA. 91. 7271-7275 (1994)
• [文献書誌] Asao,H.: "Interleukin 2-induced activation of JAK3:possible involvement in signal transduction for c-myc induction and cell proliferation." FEBS Letters. 351. 201-206 (1994)
• [文献書誌] Kondo,M.: "Expression of the mouse interleukin-2 receptor γ chain in various cell populations of thymus and spleen." Eur.J.Immunol.24. 2026-2030 (1994)
• [文献書誌] Fujii,M.: "Serum response factor has functional roles both in indirect binding to the CArG box and in the transcriptional activation function of human T-cell leukemia virus type I Tax." J.Virol.68. 7275-7283 (1994)
• [文献書誌] Uchijima,M.: "Tax protein of HTLV-1 and -2 induce expression of the gene encoding erythroid-potentiating activity(tissu inhibitor of metalloproteinases-1:TIMP-1)." J.Biol.Chem.269. 14946-14950 (1994)
• [文献書誌] Tsuchiya,H.: "Two distinct regions from a functional activation domain of the HTLV-1 trans-activator Tax1." Oncogene. 6. 337-340 (1994)
• [文献書誌] Fujita,K.: "Enhancement of T cell receptor Signaling of Tumor-infiltrating Lymphocytes by Retrovirally Mediated fyn Gene Transduction." Jpn.J.Cancer.Res.85. 1073-1079 (1994)
• [文献書誌] Akagi,T.: "Increased protein tyrosine-phosphorylation in primary T-cells transduced with Tax1 of Human T-cell leukemia virus typeI." FEBS Letters.358. 34-38 (1995)
• [文献書誌] Hirai,H.: "Tax protein of human T-cell leulemia virus type I binds to the ankyrin motifs of inhibitory factor kB and induces nuclear translocation of transcription factor NF-kB proteins for transcriptional activation." Proc.Natl.Acad.Sci.USA.91. 3584-3588 (1994)
• [文献書誌] Fujimoto,T.: "Novel isoforms of human cyclic AMP-responsive element modulator(hCREM)mRNA." J.Biochem.115. 298-303 (1994)
• [文献書誌] Yamada,T.: "The HTLV-I Tax protein induces apoptosis which is blocked by the BcI-2 protein." J.Virol.68. 3374-3379 (1994)
• [文献書誌] Inoue,H.: "Suppression of the transformed phenotype in hybrids of human T-cell leukemia virus type I Tax-transformed rat fibroblasts and normal human fibroblasts." Exp.Cell Res.215. 68-74 (1994)
• [文献書誌] Nishimura,M.: "Demonstration of human T lymphotropic virus type I(HTLV-I)-specific T cell responses from seronegative and polymerase chain reaction-negative persons exposed to HTLV-I." J.Infect.Dis.170. 334-338 (1994)
• [文献書誌] Uchiyama,T.: "Pathophysiology of adult T cell leukemia cells--cell growth characteristics-- In “Adult T cell leukemia"(ed.by K.Takatsuki)" Oxford University Press,Oxford. 181-203 (1994)
• [文献書誌] Takaori-K.: "Detection fo homing,proliferation,and infiltration sites of adult Tcelleukemiacells in severe combined immunodeficiency mice using radiometric techniques." Jpn.J.Cancer Res.,in press.(1995)
• [文献書誌] Tateno,Y.: "Genetic and functional variabilities in the human immunodeficiency virus type 1 isolated from the same blood samples with and without CD8+ cells." Immunology & Infectious Disease. 4. 41-46 (1994)
• [文献書誌] Kitamura,M.: "Expression of an endogenous retroviral gene product in human placenta." Int.J.Cancer. 58. 836-840 (1994)
• [文献書誌] Seto,K.: "A rat model of HTLV-I infection.Development of chronic progressive myeloneuropathy in seropositive WKAH rats and related apoptosis." Acta Neuropahol.,. (in press.).
• [文献書誌] Takeuchi,K.: "Expression of endogenous retroviruses,ERV3 and 14-1,in synovial tissues from patients with rheumatoid arthritis." Ciln Exp.Immunol.,. (in press.).
• [文献書誌] Sakai, R.: "A novel signaling molecule,p130,forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner." EMBOJ.13. 3748-3756 (1994)
• [文献書誌] Sakai, R.: "Characterization and purification of p130,the main phosphoprotein associated with v-Crk oncoprotein." J.Biol.Chem.269. 32740-23746 (1994)
• [文献書誌] Okumura,N.: "Vasoactive intestinal peptide induces differentiation and MAP kinase activation in PC12h cells." J.Biochem.115. 304-308 (1994)
• [文献書誌] Okumura,N.: "Vasoactive intestinal peptide induces tyrosine phosphorylation in PC12th cells." J.Biochem.116. 341-345 (1994)
• [文献書誌] Miyake,K.: "Murine B cell Proliferation and Protection from Apoptosis with an Antibody against a 105-kD Molecule:Unresponsiveness of X-linked Immunodeficient B cells." J.Exp.Med.180. 1217-1224 (1994)
• [文献書誌] Sato,S.: "IL-5 receptor-mediated tyrosine phosphorylation of SH2/SH3-containing proteins and activation of Bruton's tyrosine and Janus 2 kinases." J.Exp.Med.180. 2101-2111 (1994)
• [文献書誌] Tomida,S.: "Intercellular adhesion molecule-1 and leukocyte function-associated antigen-I are involved in protection mediated by CD3+TCRab- T cells at the early stage after infection with Listeria monocytogenes in rats." Int.Immunol.6. 955-961 (1994)
• [文献書誌] Ohtsuka,K.: "Similarities and differences between extrathymic T cells residing in mouse liver and intestine." Cell Immunol.153. 52-66 (1994)
• [文献書誌] Hiromatsu,K.: "Increased Fas antigen expression in murine retrovirus-induced immunodeficiency syndrome,MAIDS." Eur.J.Immunol.24. 2446-2451 (1994)
• [文献書誌] Aoki,Y.: "Clonal expansion but lack of subsequent clonal deletion of bacterial superantigen-reactive T cells in murine retroviral infection." J.Immunol.153. 3611-3621 (1994)